The Department of Chemical and Systems Biology Presents

Helle D. Ulrich, Ph.D.
Professor, Institute of Molecular Biology (IMB), Mainz, Germany

Talk Title: “Reprogramming the Ubiquitin Code – Polyubiquitin Chain Engineering with Tailor-made Enzymes”

Abstract: The small posttranslational modifier, ubiquitin, regulates many aspects of cellular metabolism, ranging from protein quality control via cell cycle progression to DNA repair and the inflammatory response. It generally acts by modulating the stability, localization, or molecular interactions of its targets. Its versatility as a signaling molecule derives to a large extent from its ability to form polymeric chains of varying topologies, depending on how the ubiquitin moieties are linked to each other, and from a multitude of effector proteins that recognize the modified target proteins in a more or less linkage-selective manner. The complexity of polyubiquitin chain structures and their read-out by such ubiquitin receptors is collectively called the ‘ubiquitin code’.

Insight into this code has come from various analytical tools, including linkage-specific antibodies and proteomic analysis; however, the relevance of a specific polyubiquitin chain linkage for a particular ubiquitylation event is often poorly understood because the linkage is inherent in the enzymes involved in the modification and therefore cannot be altered. Moreover, we currently lack the tools to afford the modification of a protein of interest with a particular type of chain on demand. We have now designed an inducible, linkage-selective polyubiquitylation tool, named ‘Ubiquiton’, for the reprogramming or de novo addition of polyubiquitin chains in vitro or in vivo. Here I will present proof-of-principle experiments showing the validation of our system and its application to targets relevant to DNA replication stress management and the endocytic pathway.

Reading Material:

1. Linkage reprogramming by tailor-made E3s reveals polyubiquitin chain requirements in DNA-damage bypass.
   Wegmann S, Meister C, Renz C, Yakoub G, Wollscheid HP, Takahashi DT, Mikicic I, Beli P, Ulrich HD. Mol Cell 2022 Mar 3:S1097-2765(22)00139-3.
   doi: 10.1016/j.molcel.2022.02.016
2. Fast friends – Ubiquitin-like modifiers as engineered fusion partners.
   Asimaki E, Petriukov K, Renz C, Meister C, Ulrich HD. Semin Cell Dev Biol 2021 Nov 25:S1084-9521(21)00289-5.
   doi: 10.1016/j.semcdb.2021.11.013

Zoom Call Information

Topic: CSB Cutting Lecture Series: Helle D. Ulrich, PhD
Time: Apr 15, 2022 12:30 PM Pacific Time (US and Canada)

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